Prognostic factors in retroperitoneal fibrosis.

The aim of this study is to evaluate effective prognostic factors in the evolution of patients with retroperitoneal fibrosis and to establish the validity of fractal analysis in determining the disease severity in these patients. Material and Methods: This study included 19 patients (M/F: 5/14) treated for idiopathic retroperitoneal fibrosis and bilateral obstructive renal failure between Jan 2004–Dec 2008. Patients were identified retrospectively, searching for patients diagnosed with IRF, after retroperitoneal biopsy or, in most cases the diagnosis rested on radiological findings, especially CT, with identification of a retroperitoneal mass, the absence of other demonstrable renal or ureteric disease or any other pathology that could explain the findings. CT was very useful in describing the retroperitoneal mass around the aorta and inferior vena cava, the extent of the lesion and for monitoring the response to surgical treatment during the follow–up. The data were evaluated about medical history, physical examination findings, laboratory tests (serum urea and creatinine, blood sugar, sodium, potassium, bicarbonate levels, serum pH, uric acid, haematocrit, white blood cell count), imaging methods (renal ultrasound, abdominal CT–scan, MRI). At admission all patients had active disease with obstructive renal failure and underwent bilateral ureteric stenting in order to normalize the BUN levels. After normalizing of BUN levels, ureterolysis and omental wrapping was performed. Postoperatively, ureteric stents were removed after 1 month and remission of renal disfunction was obtained in approximately 5 months (range 2–10 months). All patients were followed for at least 1 year. Patients were regularly checked every 3 months. Results: Of the 19 patients, there were 5 men and 14 women. The median age at diagnosis of RF was 50 years (range 42–64 years). The most frequent presenting symptoms were back or abdominal pain, weakness, weight loss, oligoanuria, arterial hypertension and mild fever. The duration of symptoms before diagnosis ranged from 6 to 18 months. At presentation all patients had active disease, presenting renal dysfunction with a median serum creatinine of 5.18 mg/dl (range 1–15.4 mg/dl). Most of the patients had moderate bilateral hydronephrosis (2nd degree hydronephrosis). In our study, all patients had excellent prognosis, with full recovery of renal function in 78% of cases (15 patients). The fractal dimension of the fibrosis mass contour correlates with level of renal function impairment. Even more, the fractal dimension seems to slightly variate between CT evaluations (1.30±0.1), suggesting a non aggressive pattern of extension of the fibrotic mass characteristic for benign lesions. Conclusions: The imaging parameters did not predict the disease severity, except the increase in fractal dimension of fibrosis surface area. Efficacy of bilateral ureteric stenting in improving renal function is limited in most of the cases. Dispite the level of renal function impairment at admission, full recovery can be achieved after bilateral ureteric stenting/nephrostomy and ureterolisis.


Introduction
Retroperitoneal fibrosis (RPF) was first described in 1905 by the French urologist Albaran, but it became fully recognized in 1948, with the classic publication by Ormond [1]. Although its true incidence is unknown, estimates range from one case per 200,000 to 500,000 individuals per year. [2] It occurs predominantly in men in their fifth and sixth decades of life, with a 3:1 male/female ratio, and no ethnic predisposition. [3] Retroperitoneal fibrosis is generally idiopathic, but can also be secondary to the use of certain drugs, malignant diseases, infections and surgery. The idiopathic form of the disease accounts for more than two thirds of cases and it is characterized by a white, woody and fibrous plaque that covers the retroperitoneal structures, i.e. the great vessels, ureters and the psoas muscle. It is usually centralized at the level of the fourth and fifth lumbar vertebrae and spread down to the pelvis; rarely, it extends into the roots of the mesentery, scrotum or continues above the diaphragm as fibrous mediastinitis. [1][2][3] The clinical presentation of IRF is usually insidious with vague constitutional symptoms and generally low back pain that may be severe and non-responsive to antiinflammatory drugs. The pathogenesis is still poorly elucidated, but recent evidence supports the hypothesis that the disease may be the result of an inflammatory state triggered by autoimmune responses [8][9][10]. Parum et al. [8], considering the high correlation of IRF with atheromatous peri-aortitis, considers that the disease may be due to an immune reaction to some components of atherosclerotic plaques such as low-density lipoprotein (LDL) and ceroid.
The introduction of medical therapy, mainly based on corticosteroids, has greatly improved patients' outcome, [5,6] and the availability of imaging techniques, such as computer tomography (CT) and magnetic resonance imaging (MRI), has provided non-invasive and reliable methods of diagnosis and follow-up. [7] The aim of this study is to evaluate effective prognostic factors in the evolution of patients with retroperitoneal fibrosis and to establish the validity of fractal analysis in determining the disease severity in these patients. Both surgical and medical managements have been used in IRF. There are two main approaches; the first consists of surgical relief of the obstruction by ureterolysis (open or laparoscopic) with or without omental wrapping of the ureter, followed or not by corticosteroid therapy [6]. The second consists of relieving the obstruction by placing ureteric stent(s), followed by corticosteroid therapy alone or together with azathioprine or tamoxifen [6]. However, there are no prospective randomized trials to compare the two alternatives.

Material and methods
This study included 19 patients (M/F: 5/14) treated for idiopathic retroperitoneal fibrosis and bilateral obstructive renal failure between Jan 2004-Dec 2008. Patients were identified retrospectively, by searching for the ones diagnosed with IRF, after retroperitoneal biopsy or, in most cases the diagnosis resting on radiological findings, especially CT, with the identification of a retroperitoneal mass, the absence of other demonstrable renal or ureteric disease or any other pathology that could explain the findings. CT was very useful in describing the retroperitoneal mass around the aorta and inferior vena cava, the extent of the lesion and for monitoring the response to surgical treatment during the follow-up. The data about medical history, physical examination findings, laboratory tests (serum urea and creatinine, blood sugar, sodium, potassium, bicarbonate levels, serum pH, uric acid, haematocrit, white blood cell count), imaging methods (renal echography, abdominal CT-scan, MRI) were evaluated.
All patients were followed for at least 1 year. Patients were regularly checked at every 3 months. At each control, patients were submitted to clinical examination and to the following laboratory tests: serum creatinine, complete blood cell count and urine analysis. Renal ultrasound and computed tomography (CT) were performed every 6 months until the achievement of remission. After remission, the same investigations were repeated every year.
At admission, all patients had active disease with obstructive renal failure and underwent bilateral ureteric stenting in order to normalize the BUN levels. CT scan was performed on a helical Siemens Emotions 2007 with 16 slices preoperatory in all cases and images were processed in the Department of Radiology of "Fundeni" Clinical Institute. Parameters assessed on helical CT were: level of secondary hydronephrosis, fibrosis width in the transureteric frontal section, interureteric distance at L4 intervertebral discus, maximal cranio-caudal length in frontal section of fibrosis area and the fractal dimension of fibrosis mass. According to the level of renal function impairment we used native or contrast enhanced images.
At six months, contrast CT was performed at patients with normal renal function. Maximal cranio-caudal length was calculated in frontal sections and was considered as the maximal vertical extension of the fibrotic mass. Because the ICV and the abdominal aorta are not visible on frontal reconstructive section native CT scan, we considered the ureters as landmarks and the fibrotic mass occupying the space between the 2 ureters with a lateral extension beyond the line that crosses the ureters. The ureteric distance in native CT was calculated with the help of the ureteric stents. The width of the fibrotic mass was considered the line between the lateral extensions of the fibrotic mass at L4 intervertebral discus in a longitudinal section.

Fractal analysis
In the last 10 years fractal analysis become a powerful tool for analyzing form, pattern and growth of biological systems and subsystems at microscopic and macroscopic scale [18,19]. In our case, the fractal dimension can give information on the irregularity of the contour of the fibrosis masses. This kind of details are best captured by using the box counting method which provides us with a measure -fractal dimension (Fd) of the non/ smoothness of the contour. The fractal dimension is calculated by using the "box-counting" algorithm because, in comparison to other methods, it offers two major advantages: it is easy to implement and can be applied on no matter how complex images.

Method description
The "box-counting" algorithm [20] assumes the determination of the fractal dimension in accordance with the dependence of the object contour upon the used measure scale factor. It consists of successive image coverage with grids of squares of sides 2, 4, 8. It is important to constantly count the number of squares that contain parts of the contour. The points of coordinates (log(N(s)), log(1/s)), where s is the common side of the coverage squares, and N(s) the number of squares that contain the information, will be positioned approximately in a line and its slope will be the fractal dimension in "boxcounting" sense.
Thus, the "box-counting" fractal dimension, derived from the Hausdorff coverage dimension [16,17] is given by the following approximation: , where -N(s) is the number of squares that contain information (parts of the extracted contour).
-s -side length of the squares in the coverage grid.
It is expected, that for a smaller s, the above approximation should be better, If this limit exists, it is called the "box-counting" dimension of the measured object. In practice, this limit converges slowly, that is why the following expression is used: This is the equation of a straight line of slope Fd, the "log-log" curve described by the points of (log(N(s), log(1/s)) for different values of the cube's side -s. Through linear regression (least squares method), the slope of the line that approximates the points' distribution is determined; this is the fractal dimension.
For an example of how the algorithm is used, we will consider the image of a region of the fibrosis mass for which we want to determine the fractal dimension of the contour - Fig. 1.1. Traditionally, in order to determine the contour, the pixels over certain luminosity are being neglected Fig. 1.2.a); this implies choosing a good threshold in order to capture the exact object of interest. When applying this procedure to medical images like CTs and MRIs, the errors can be larger than the extracted information itself. That is why we implemented a different method for contour extraction. The contour is captured at a series of different levels of luminosity Fig. 1.2.b) -this method leading to better performances and being a novel approach towards macroscopic medical images processing. The different levels of luminosity are chosen within the range of shades of the analyzed object. Next, we will apply the "box-counting" algorithm, described above, for different scale values s, using a software tool-MorfoFractal developed along with the contour extraction tool.
We have used images that contain those parts of the fibrosis mass that are not obstructed by nearby organs, so that we can obtain information on the free evolution of the mass. We took the CT from each patient, which contains as many such fibrosis regions and calculated the global fractal dimension.

Clinical characteristics at presentation
Out of the 19 patients, 5 were men and 14 women. The median age at diagnosis of RF was 50 years old (range 42-64 years old). The most frequent presenting symptoms were back or abdominal pain, weakness, weight loss, oligoanuria, arterial hypertension and mild fever ( Table 1). The duration of symptoms before diagnosis ranged from 6 to 18 months. At presentation all patients had active disease, presenting renal dysfunction with a median serum creatinine of 5,18 mg/dl (range 1-The diagnosis of IRF was made by CT in all patients and confirmed with a histological evaluation of the fibrotic mass. The biopsy of the mass was obtained during ureterolysis. At admission, all patients had active disease with obstructive renal failure and underwent bilateral ureteric stenting in order to normalize the BUN levels. After the normalizing of BUN levels, ureterolysis and omental wrapping was performed. Postoperatively, ureteric stents were removed after 1mth and remission of renal dysfunction was obtained in approximately 5 months (range 2-10 months).
15.4 mg/dl). Five of them had a rapidly progressive renal failure with a serum creatinine (8.2mg/dl) and were oliguric or anuric at presentation. The median haematocrit of the patients group was 33% (range 29-40%). We used bilateral ureteric stenting for all patients in order not only to normalize the BUN levels, but also to establish the landmarks on the native CT and to facilitate intraoperative dissection of the ureters. Five of our patients needed unilateral percutaneous nephrosthomy due to the inefficiency of bilateral stenting. Most of the patients had moderate bilateral hydronephrosis (2 nd degree hydronephrosis). In our study, all patients had excellent prognosis, with full recovery of renal function in 15 patients (78%).
The fractal dimension of the fibrosis mass correlates with the level of renal function impairment suggested by the creatinine level. Generally, in the case of preoperatory analyzed CTs, if the creatinine value is high, the fractal dimension is higher too, but the rate of increase in the case of Fd is lower as it can be deduced from Fig 3. This fact leads to our statement that the more aggressive the fibrosis (high Fd), the higher the level of renal function impairment.
The fractal dimension varies suggestively between CT evaluations in time (1.30 ±0.2), suggesting a nonaggressive pattern of extension of the fibrotic mass characteristic for benign lesions. In fact, the regression of the affected tissue width and structure complexity (Fd) can be clearly observed.
After the surgical intervention, it can be observed that the value of the fractal dimension of the mass is decreasing with approximately the same rate as the fibrosis width. The decrease in Fd results from the fact that the fibrosis contour is becoming smoother along with area diminution. Generally, the creatinine levels are dropping too, but much faster, mainly due to the presence of ureteric stents/nephrostomy.
Interureteric distance and fibrosis width at admission do not correlate with the serum creatinine value ( fig.4, fig   5.) and the recovery of the renal function, these confirming previous studies on RF.

Discussion
Malignancy was excluded based on clinical, laboratory and radiological grounds. CT scan did not show any direct sign of malignancy or indirect signs such as cranial location of the mass, anterior displacement of the aorta, lateral displacement of the ureters and/or bone destruction [13] All the patients had ureterolysis and omental wrapping. The advantages of surgery are the relief of obstruction with a recovery of renal function in about 70% of cases [11] and the possibility of taking samples of the invading mass to rule out lymphomas or metastatic cancer. However, obstruction may recur in about 22% of responders [12]. Moreover, surgery does not relieve the systemic manifestations of the disease that affect the majority of patients, symptoms that can be managed by the use of cortisone or immunosuppressive agents. Generally, however, ureterolysis remains the mainstay in treatment of this disease. The ureter is dissected free from the plaque, and in order to prevent it from being caught again by the fibrotic process laterally or intraperitoneally. An alternative procedure is to wrap the ureter with omentum to provide an effective barrier against reentrapment by the fibrosis [15]. Postoperative CT in cases in which an omental wrap has been used shows a lowattenuation halo surrounding the opaque ureter [15].

Fig.3 Creatinine vs. Fractal dimension
Patients who have had ureterolysis commonly have a lateral bowing of the mid-portion of the ureter(s) [15]. Long-term follow-up with CT usually shows a progressive decrease in the size of the plaque, especially in patients treated with corticosteroids. However, the majority of patients will have a small residual mass that can persist for months to years [14].   Figure  B, full remission of fibrotic mass at 6 months after surgery.
Neither sufficient information is available on the long-term outcome of patients with RF, nor is there any study that compares the efficacy of different therapeutic options. In our study, most of our patients had excellent prognosis, with full recovery of renal function in 15 patients (78%). Four of our patients remained with one functional kidney, 2 required permanent ureteric stent and 2 nephrostomy with a mild but stable renal insufficiency (serum creatinine level >1.5 mg/dl).

Conclusions
The imaging parameters did not predict the disease severity, except for the increase in fractal dimension of fibrosis surface area. Efficacy of bilateral ureteric stenting in improving renal function is limited in most of the cases. Despite the level of renal function impairment at admission, full recovery can be achieved after bilateral ureteric stenting/nephrostomy and ureterolisis. However, as renal insufficiency may persist and local reactivations or other possible complications of the disease may occur, patients with IRF should be regularly monitored by CT scan at 6 months and should receive a prompt therapeutical intervention in order to treat the recurrences of the disease.